Death from coronary heart disease remains the major medical problem in affluent countries. Obesity predisposes to diabetes, increases the tendency to hypertension, atherosclerosis and contributes to ischemic heart disease. Body weight and level of body fat or set point in the adipose tissue mass is maintained over long periods of time in adult animals, despite changes in food intake and activity. Additionally, body weight and level of body fat are defended against changes by overfeeding and fasting. Obesity is caused by some "intrinsic" abnormality, which leads to hyperphagia and increased accumulation of body fat. Once body weight and the level of body fat is stabilized, the obese state is defended against change by overeating or fasting. It is proposd to secure information on the physiological and biochemical mechanisms that 1) maintain "normal" body weight and "normal" levels of body fat; 2) "intrinsic" abnormalities which cause obesity; 3) reverse or correct these abnormalities and restore "normal" body weight and "normal" levels of body fat. It is proposed to study the mechanisms that maintain the level of fat in the adipose tissue mass. This is effected by two reciprocally inhibitory processes, mechanisms that increase the amount of body fat and those that reduce the amount in the depots. The following studies will be made: 1) measure activity of hormone-sensitive lipase and lipoprotein lipase in adipose tissue; 2) examine the effect of cyclic AMP and prostaglandins (PGE1) upon lipolysis and loss of body fat on the one hand and upon lipogenesis which stimulates the accretion of body fat on the other; 3) effect of insulin on lipogenesis and lipoprotein lipase activity and its effect upon the activity of hormone-sensitive lipase, adenylcyclase, phosphodiesterase as they affect the levels of cyclic AMP in the adipose tissues; 4) determine the loss, elicited by hypothalamic lesions, of hypothalamic releasing factors, and of the hormones of the pituitary and its target glands; 5) attempt to reverse obesity and hyperphagia elicited by hypothalamic lesions by the restoration of hypothalamic releasing factors and reduce the incidence of vascular disease.